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Inhibition of the Prohormone Convertase Subtilisin-Kexin Isoenzyme-1 Induces Apoptosis in Human Melanoma Cells.
MedLine Citation:
PMID:  23884247     Owner:  NLM     Status:  Publisher    
Prohormone convertases (PCs) are endoproteases that process many substrates in addition to hormone precursors. Although overexpression of PCs is linked to carcinogenesis in some solid tumors, the role of subtilisin-kexin isoenzyme-1 (SKI-1) in this context is unknown. We show that SKI-1 is constitutively expressed in human pigment cells with higher SKI activity in seven out of eight melanoma cell lines compared with normal melanocytes. SKI-1 immunoreactivity is also detectable in tumor cells of melanoma metastases. Moreover, tissue samples of the latter display higher SKI-1 mRNA levels and activity than normal skin. From various stimuli tested, 12-O-tetradecanoylphorbol-13-acetate and tunicamycin affected SKI-1 expression. Importantly, SKI-1 inhibition by the cell-permeable enzyme inhibitor decanoyl-RRLL-chloromethylketone (dec-RRLL-CMK) not only suppressed proliferation and metabolic activity of melanoma cells in vitro but also reduced tumor growth of melanoma cells injected intracutaneously into immunodeficient mice. Mechanistic studies revealed that dec-RRLL-CMK induces classical apoptosis of melanoma cells in vitro and affects expression of several SKI-1 target genes including activating transcription factor 6 (ATF6). However, ATF6 gene silencing does not result in apoptosis of melanoma cells, suggesting that dec-RRLL-CMK induces cell death in an ATF6-independent manner. Our findings encourage further studies on SKI-1 as a potential target for melanoma therapy.Journal of Investigative Dermatology advance online publication, 25 July 2013; doi:10.1038/jid.2013.282.
Nina Weiß; Agatha Stegemann; Marwa A T Elsayed; Karin U Schallreuter; Thomas A Luger; Karin Loser; Dieter Metze; Carsten Weishaupt; Markus Böhm
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-6-27
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  -     ISSN:  1523-1747     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-7-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University of Münster, Münster, Germany.
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